Emerging Success With Novel Targeted Therapies in Endocrine-Resistant Metastatic Breast Cancer

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In hormone receptor–positive breast cancer, the ability to successfully target key mediators of endocrine resistance is changing the outlook of metastatic disease in this subtype, according to Aditya Bardia, MD, MPH, FASCO, Director of Breast Cancer Research and Associate Professor at Harvard Medical School, and Attending Physician at Mass General Cancer Center, Boston.

Two major pathways confer resistance to endocrine therapies for breast cancer. One is the endocrine receptor pathway itself, wherein the ESR1 mutation confers estrogen-independent, endocrine receptor–mediated signaling. The other is the upstream growth factor signaling pathway, which confers endocrine receptor–independent signaling, and presents therapeutic opportunities for targeting PI3K, AKT, and mTOR. With new agents showing activity, outcomes are expected to improve for patients with metastatic breast cancer who develop resistance to standard endocrine therapy, Dr. Bardia said in a lecture at the 2023 Miami Breast Cancer Conference.1

Targeting PI3K

Endocrine therapy plus alpelisib, a PI3K inhibitor, is approved for patients with metastatic hormone receptor–positive, HER2-negative, PI3KC-mutant tumors. Alpelisib was combined with fulvestrant in the global phase III SOLAR-1 trial.2 A significant improvement was demonstrated in progression-free survival (hazard ratio [HR] = 0.65; P < .001), and there was a trend toward better overall survival with the combination therapy. The findings led to approval of this regimen by the U.S. Food and Drug Administration (FDA) for patients with PIK3CA-mutant hormone receptor–positive metastatic breast cancer.

“There is interest in moving these triplet combinations [fulvestrant, a CDK4/6 inhibitor, and an AKT inhibitor] into the first-line setting.”
— Aditya Bardia, MD, MPH, FASCO

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The subsequent BYLieve trial asked the question of whether alpelisib plus fulvestrant would be beneficial in patients who had received cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, which had become standard therapy after SOLAR-1 completed enrollment.3 The benefits seen in SOLAR-1 were sustained, with a clinical benefit rate of 50% at 6 months and a median progression-free survival of 7.3 months. Alpelisib still has value, therefore, in the post-CDK4/6 inhibitor setting, noted Dr. Bardia.

Regarding the safety of alpelisib, the drug’s main toxicities are hyperglycemia, diarrhea, and rash, for which the rates of grade 3 adverse events were 33% (and 4% grade 4), 7%, and 20%, respectively. For all grades, more than half of patients experienced these toxicities.

“Hyperglycemia is an on-target effect because insulin signaling is through the PI3K pathway. Blockade of this pathway can confer relative insulin resistance, which may cause hyperglycemia,” Dr. Bardia explained. “Alpelisib was a start. It’s the first PI3K inhibitor that’s FDA-approved, but given the side effects, particularly hyperglycemia, there is interest in developing novel [more selective] PI3K inhibitors that would have a lower toxicity profile.”

In this category are inavolisib, whose mechanism involves ATP binding, and novel allosteric PIK3CA-mutant–specific inhibitors, including LOXO-783 and RLY-2608. Inavolisib is in late-stage development. The allosteric inhibitors target the mutant PI3K and have limited impact on wild-type PI3K. The more specific mutant targeting will hopefully improve tolerability, especially with regard to hyperglycemia.

AKT Inhibitors

Endocrine therapy plus capivasertib is expected to be approved for hormone receptor–positive, HER2-negative tumors. Targeting of the AKT pathway with capivasertib plus fulvestrant proved beneficial in the FAKTION trial,4 significantly reducing the risk of disease progression in the second-line setting (HR = 0.56; P = .0023) and justifying the subsequent phase III CAPItello-291 trial, for which results were recently presented.5

In CAPItello-291, median progression-free survival was more than doubled, from 3.6 months with fulvestrant (HR = 0.60; P < .001) to 7.2 months with capivasertib plus fulvestrant. In patients with AKT alterations, median progression-free survival was 3.1 months vs 7.3 months, respectively (HR = 0.50; P < .001). Trends in overall survival were also observed in both the overall and AKT-altered populations, but the survival results were only 28% mature.

The main side effect with capivasertib is diarrhea, which was seen in approximately 75% of patients in CAPItello-291, but it was grade 3 in 9%. The second most common side effects was nausea, reported in approximately 35%. “The side effects we usually see with the PI3K inhibitors, especially hyperglycemia, were not common with capivasertib. The incidence of rash was also low. That’s a potential advantage with AKT inhibitors,” Dr. Bardia noted.

Interest in Triplet Combinations

Triplet combinations that combine fulvestrant with a CDK4/6 inhibitor and an AKT inhibitor are also being evaluated. The investigator-initiated TAKTIC trial combined fulvestrant, the CDK4/6 inhibitor palbociclib, and the AKT inhibitor ipatasertib in various schedules and doses; preliminary evidence of clinical activity has been shown with this triplet.6 “There is interest in moving triplet combinations into the first-line setting,” noted Dr. Bardia.

mTOR Inhibitors

Endocrine therapy plus everolimus is approved for all-comers with hormone receptor–positive, HER2-negative metastatic disease. The mTOR inhibitor everolimus was combined with exemestane in the BOLERO-2 trial, yielding a doubling in median progression-free survival, from 4.1 months with exemestane alone to 10.6 months with the addition of everolimus (HR = 0.36; P < .001).7 These findings led to FDA approval of this combination.

“This trial occurred at a time when we didn’t have much understanding of ESR1 mutations. It used exemestane as the endocrine backbone. Maybe today, we would have considered fulvestrant (a selective estrogen receptor degrader [SERD]) plus everolimus in the setting beyond the second line,” he said. Perhaps, because exemestane was the endocrine partner in BOLERO-2, outcomes in both arms were much better in patients with wild-type tumors than in those with ESR1 mutations.8 There also appeared to be some differences in outcomes based on whether the ESR1 mutation was D538G or Y5375, Dr. Bardia said, but noted conclusions cannot be drawn from these small subsets.

Studies have suggested that better results may be achieved with targeted therapy in which a SERD is the endocrine partner. This approach is being evaluated in the ELEVATE trial, an umbrella study looking at the safety and efficacy of elacestrant in combination with alpelisib, everolimus, palbociclib, abemaciclib, and ribociclib. 

DISCLOSURE: Dr. Bardia has served as a consultant or advisor to Daiichi/AstraZeneca, Eli Lilly, Foundation Medicine, Genentech/Roche, Immunomedics/Gilead Sciences, Merck, Novartis, Pfizer, Phillips, Radius Health/Menarini, Spectrum Pharma, Taiho Pharm, and Sanofi.


1. Bardia A: Targeting the PI3K/AKT/mTOR axis. Invited Lecture. 2023 Miami Breast Cancer Conference. Presented March 3, 2023.

2. André F, Ciruelos E, Rubovszky G, et al: Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 380:1929-1940, 2019.

3. Rugo HS, Lerebours F, Ciruelos E, et al: Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol 22:489-498, 2021.

4. Howell SJ, Casbard A, Carucci M, et al: Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): Overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial. Lancet Oncol 23:851-864, 2022.

5. Turner N, Oliveria M, Howell SJ, et al: Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Results from the phase III CAPItello-291 trial. 2022 San Antonio Breast Cancer Symposium; Abstract GS3-04. Presented December 8, 2022.

6. Wander S, Micalizzi D, Dubash T, et al: AKT inhibition in combination with endocrine therapy and a CDK4/6 inhibitor (CDK4/6i) in patients with hormone receptor positive/HER2 negative metastatic breast cancer and prior CDK4/6i exposure: A translational investigation. 2021 San Antonio Breast Cancer Symposium. Abstract P1-18-22. Presented December 8, 2021.

7. Baselga J, Campone M, Piccart M, et al: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520-529, 2012.

8. Chandarlapaty S, Chen D, He W, et al: Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: A secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol 2:1310-1315, 2016.